My morning serum cortisol is 5 µg/dL; what interventions are indicated?

Morning Cortisol 5.0 µg/dL: Immediate Diagnostic Workup and Treatment Required

A morning serum cortisol of 5.0 µg/dL is definitively abnormal and requires urgent ACTH measurement, cosyntropin stimulation testing, and probable initiation of glucocorticoid replacement therapy. 1, 2

Immediate Diagnostic Steps

Obtain ACTH Level Urgently

• Measure plasma ACTH immediately to distinguish primary from secondary adrenal insufficiency—this is the critical first step after identifying a low morning cortisol 3, 1, 2

• High ACTH (>300 pg/mL) with cortisol <5 µg/dL is diagnostic of primary adrenal insufficiency (Addison's disease), indicating destruction of the adrenal glands themselves 3, 2

• Low or inappropriately normal ACTH with low cortisol indicates secondary adrenal insufficiency, pointing to pituitary or hypothalamic dysfunction 3, 1, 2

Perform Cosyntropin Stimulation Test

• Administer 0.25 mg (250 mcg) cosyntropin IV or IM with cortisol measurements at baseline, 30 minutes, and 60 minutes post-administration 3, 4

• **Peak cortisol <500 nmol/L (<18 µg/dL) at 30 or 60 minutes confirms adrenal insufficiency**, while >550 nmol/L (>18-20 µg/dL) excludes the diagnosis 3, 4, 2

• Important caveat: If the patient is clinically unstable with hypotension, nausea/vomiting, or altered mental status, do NOT delay treatment for diagnostic testing—give IV hydrocortisone 100 mg immediately plus 0.9% saline infusion at 1 L/hour 3, 1

Check for Confounding Medications

Stop These Drugs Before Testing

• Glucocorticoids and spironolactone must be stopped on the day of testing, as they falsely elevate cortisol levels 4

• Estrogen-containing medications should be stopped 4-6 weeks before testing, as they increase cortisol-binding globulin and artificially raise total cortisol 4

• Long-acting glucocorticoids (e.g., dexamethasone) require longer washout periods before accurate testing can be performed 4

Recognize Iatrogenic Causes

• Any patient taking ≥20 mg/day prednisone or equivalent for ≥3 weeks is at high risk for iatrogenic secondary adrenal insufficiency and should be presumed to have suppressed HPA axis function 3

• Morning cortisol measurements in patients actively taking corticosteroids are not diagnostic because the assay measures both endogenous and therapeutic steroids with variable cross-reactivity 3

Etiologic Workup Based on ACTH Results

If ACTH is Elevated (Primary Adrenal Insufficiency)

• Measure 21-hydroxylase (anti-adrenal) autoantibodies first, as autoimmune destruction accounts for ~85% of primary adrenal insufficiency in Western populations 3

• If autoantibodies are negative, obtain CT imaging of the adrenals to evaluate for hemorrhage, tumors, tuberculosis, fungal infections, or other structural causes 3

• In males with negative antibodies, assay very long-chain fatty acids (VLCFA) to screen for adrenoleukodystrophy 3

If ACTH is Low or Normal (Secondary Adrenal Insufficiency)

• Evaluate for pituitary pathology including tumors, hemorrhage, hypophysitis (especially in patients on immune checkpoint inhibitors), sarcoidosis, or hemochromatosis 3, 2

• Assess other pituitary hormone axes (TSH, LH/FSH, prolactin, IGH-1) to identify broader hypopituitarism 3

• Review medication history for opioids or other drugs that suppress corticotropin production 2

Initiate Glucocorticoid Replacement Therapy

Standard Maintenance Dosing

• Hydrocortisone 15-25 mg daily in divided doses is the preferred regimen, typically given as 10 mg at 7:00 AM, 5 mg at 12:00 PM, and 2.5-5 mg at 4:00 PM to approximate physiological cortisol secretion 5, 1, 2

• Alternative regimens include cortisone acetate 25-37.5 mg daily or prednisone 3-5 mg daily, though hydrocortisone is preferred because it allows recreation of the diurnal cortisol rhythm 5, 3, 2

• Avoid dexamethasone for chronic replacement therapy, as it lacks mineralocorticoid activity and has an excessively long half-life 5, 3

Add Mineralocorticoid for Primary Adrenal Insufficiency

• Fludrocortisone 50-200 µg daily is required for primary adrenal insufficiency to replace aldosterone and maintain blood pressure and sodium balance 5, 3, 2

• Monitor adequacy by assessing salt cravings, orthostatic blood pressure, peripheral edema, and plasma renin activity, adjusting the dose as needed 3

• Advise unrestricted sodium salt intake and avoidance of potassium-containing salt substitutes 5

• Secondary adrenal insufficiency does NOT require mineralocorticoid replacement, as the renin-angiotensin-aldosterone system remains intact 3

Critical Patient Education and Safety Measures

Stress Dosing Instructions

• Patients must double or triple their usual dose during illness, fever, or physical stress to prevent adrenal crisis 3, 2

• Prescribe an emergency injectable hydrocortisone 100 mg IM kit and provide self-injection training for use during vomiting, severe illness, or inability to take oral medications 3, 2

Emergency Identification

• All patients must wear a medical alert bracelet or necklace indicating adrenal insufficiency to trigger stress-dose administration by emergency personnel 3, 2

• Provide a steroid emergency card to quickly convey diagnosis and treatment needs 3

Recognize Adrenal Crisis Warning Signs

• Severe weakness, nausea/vomiting, abdominal pain, confusion, hypotension, or shock require immediate IV hydrocortisone 100 mg plus aggressive saline resuscitation 3, 2

• Never delay treatment of suspected adrenal crisis for diagnostic procedures—mortality is high if untreated 3, 1

Drug Interactions Requiring Dose Adjustment

Medications That Increase Hydrocortisone Requirements

• CYP3A4 inducers (phenytoin, carbamazepine, phenobarbital, rifampin, other antituberculosis drugs) increase cortisol clearance and may necessitate higher replacement doses 5, 3

• Etomidate and topiramate also increase hydrocortisone requirements 5

Medications That Decrease Hydrocortisone Requirements

• CYP3A4 inhibitors (grapefruit juice, licorice) decrease cortisol clearance and may require dose reduction 5, 3

Monitoring and Long-Term Management

Clinical Assessment is Primary

• Plasma ACTH and serum cortisol are NOT useful for dose adjustment—monitoring relies predominantly on clinical assessment 5

• Signs of over-replacement include weight gain, insomnia, and peripheral edema, indicating need for dose reduction 5

• Signs of under-replacement include lethargy, nausea, poor appetite, weight loss, and increased pigmentation, suggesting insufficient dosing 5

• Fine-tune dosing by detailed questioning about daily energy levels, mental concentration, daytime somnolence, and timing of fatigue 5

Annual Follow-Up

• Review at least annually with assessment of health, well-being, weight, blood pressure, and serum electrolytes 3

• Screen periodically for new autoimmune disorders (thyroid function, diabetes, pernicious anemia, celiac disease), as autoimmune adrenal insufficiency frequently coexists with other autoimmune conditions 3

• Monitor bone mineral density every 3-5 years to assess for complications of glucocorticoid therapy 3

Common Pitfalls to Avoid

• Do not rely on electrolyte abnormalities alone—hyponatremia is present in 90% of cases, but hyperkalemia occurs in only ~50% of primary adrenal insufficiency cases 3

• Never attempt to discontinue hydrocortisone in patients with confirmed primary or secondary adrenal insufficiency from non-iatrogenic causes—these conditions are permanent and stopping replacement will precipitate life-threatening adrenal crisis 3

• When treating concurrent hypothyroidism and adrenal insufficiency, start corticosteroids several days before initiating thyroid hormone replacement to prevent precipitating adrenal crisis 3

• Approximately 10% of patients with primary adrenal insufficiency present with normal cortisol concentrations—normal to high basal cortisol with clearly elevated ACTH is still indicative of early Addison's disease when the clinical history is suggestive 6